In biology, signal transduction refers to a process by which a cell converts one kind of signal or stimulus into another. It involves ordered sequences of biochemical reactions inside the cell. These cascades of react...In biology, signal transduction refers to a process by which a cell converts one kind of signal or stimulus into another. It involves ordered sequences of biochemical reactions inside the cell. These cascades of reactions are carried out by enzymes and activated by second messengers. Signal transduction pathways are complex in nature. Each pathway is responsible for tuning one or more biological functions in the intracellular environment as well as more than one pathway interact among themselves to carry forward a single biological function. Such kind of behavior of these pathways makes understanding difficult. Hence, for the sake of simplicity, they need to be partitioned into smaller modules and then analyzed. We took VEGF signaling pathway, which is responsible for angiogenesis for this kind of modularized study. Modules were obtained by applying the algorithm of Nayak and De (Nayak and De, 2007) for different complexity values. These sets of modules were compared among themselves to get the best set of modules for an optimal complexity value. The best set of modules compared with four different partitioning algorithms namely, Farhat’s (Farhat, 1998), Greedy (Chartrand and Oellermann, 1993), Kernighan-Lin’s (Kernighan and Lin, 1970) and Newman’s community finding algorithm (Newman, 2006). These comparisons enabled us to decide which of the aforementioned algorithms was the best one to create partitions from human VEGF signaling pathway. The optimal complexity value, on which the best set of modules was obtained, was used to get modules from different species for comparative study. Comparison among these modules would shed light on the trend of development of VEGF signaling pathway over these species.展开更多
OBJECTIVE: To explore the effect of two dominating signaling pathways, VEGF/KDR and angiopoietins/Tie2, on the formation of new blood vessel in hepatocellular carcinoma (HCC) growth and metastasis. METHODS: RT-PCR and...OBJECTIVE: To explore the effect of two dominating signaling pathways, VEGF/KDR and angiopoietins/Tie2, on the formation of new blood vessel in hepatocellular carcinoma (HCC) growth and metastasis. METHODS: RT-PCR and Western blot were employed to evaluate the VEGF/KDR and angiopoietins/Tie2 expression in samples from 23 patients with HCC. Meanwhile, microvessel density (MVD) was determined as a marker of angiogenesis by counting CD34 positive cells with the method of immunohistochemistry. RESULTS: The two pathways were activated in all HCC samples. The expressions of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) were significantly higher (P<0.05) in hepatocellular carcinoma tissues and the margin of the tumor than those in control groups, and so did CD34 positive cells. Although significant difference in the expression of kinase insert domain containing receptor (KDR) and Ang1/Tie2 was not observed in all groups, their distinct high levels were seen in hepatoma and its margin compared with normal and cirrhotic liver. VEGF and Ang2 expressions were seen up-regulated in HCC with vascular invasion and satellite lesion. CONCLUSIONS: The two signaling pathways, VEGF/KDR and angiopoietins/Tie2 are activated in the process of angiogenesis in HCC and modulate the formation of new blood vessels. The imparity of the two signaling pathways' activation is to benefit HCC metastasis. In the two pathways, VEGF and Ang2 may play an important role in the process of angiogenesis, and are necessary indicators for the prognosis and metastasis of HCC. This study provides another clue for the exploration of anti-angiogenic agents.展开更多
There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, alt...There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxlainducible factor-1 （HIF-1α）. Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase （PI3K）/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT （pAKT） protein staining than did benign ovarian cystadenoma samples （p 〈 0.01）. The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursulug effective treatment against this disease.展开更多
Angiogenesis in atherosclerosis(AS)promotes plaque destabilization.miR-126 has a significant role in angiogenesis.Tetramethylpyrazine(TMP)and paeoniflorin(PF)have anti-atherosclerotic effects.However,the miR-126-relat...Angiogenesis in atherosclerosis(AS)promotes plaque destabilization.miR-126 has a significant role in angiogenesis.Tetramethylpyrazine(TMP)and paeoniflorin(PF)have anti-atherosclerotic effects.However,the miR-126-related mechanisms of TMP and PF combination(TMP-PF)on angiogenesis in AS have not been understood.To explore the mechanism of TMP-PF on angiogenesis in AS targeting miR-126.Human umbilical vein endothelial cells(HUVECs)were assigned into the control,model,TMP-PF,TMP-PF+miR-126 inhibitor,and simvastatin groups.HUVECs were transfected with miR-126 inhibitor or negative control,incubated with oxidized low-density lipoprotein(ox-LDL)to establish AS model,and then treated with TMP-PF or simvastatin.Cell proliferation,migration,and tube formation assays are conducted,and the expression of angiogenesis-related factors were detected by enzyme-linked immunosorbent assay(ELISA)and Western blotting.The expression level of miR-126 was confirmed by polymerase chain reaction(PCR).0x-LDL promoted HUVECs proliferation,migration,and tube formation,downregulated miR-126 expression,and increased the expression of VEGF,VEGFR2,bFGF,and FGFR1.TMP-PF inhibited proliferation,migration,and tube formation,upregulated miR-126 expression and decreased the expression of VEGF,VEGFR2,bFGF,and FGFR1 in ox-LDL-induced HUVECs.However,the effects of TMP-PF on angiogenesis and the expression of miR-126,VEGF,VEGFR2,and FGFR1 were abolished by miR-126 inhibitor.TMP-PF suppressed angiogenesis in AS by regulating miR-126/VEGF/VEGFR2 pathway,which might elucidate the underlying mechanism of TMP-PF in alleviating AS.展开更多
The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interactio...The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5-80 mu mol/E) for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal stmcture of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and pi-pi stacking interactions with Va1848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain inj...Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.展开更多
文摘In biology, signal transduction refers to a process by which a cell converts one kind of signal or stimulus into another. It involves ordered sequences of biochemical reactions inside the cell. These cascades of reactions are carried out by enzymes and activated by second messengers. Signal transduction pathways are complex in nature. Each pathway is responsible for tuning one or more biological functions in the intracellular environment as well as more than one pathway interact among themselves to carry forward a single biological function. Such kind of behavior of these pathways makes understanding difficult. Hence, for the sake of simplicity, they need to be partitioned into smaller modules and then analyzed. We took VEGF signaling pathway, which is responsible for angiogenesis for this kind of modularized study. Modules were obtained by applying the algorithm of Nayak and De (Nayak and De, 2007) for different complexity values. These sets of modules were compared among themselves to get the best set of modules for an optimal complexity value. The best set of modules compared with four different partitioning algorithms namely, Farhat’s (Farhat, 1998), Greedy (Chartrand and Oellermann, 1993), Kernighan-Lin’s (Kernighan and Lin, 1970) and Newman’s community finding algorithm (Newman, 2006). These comparisons enabled us to decide which of the aforementioned algorithms was the best one to create partitions from human VEGF signaling pathway. The optimal complexity value, on which the best set of modules was obtained, was used to get modules from different species for comparative study. Comparison among these modules would shed light on the trend of development of VEGF signaling pathway over these species.
文摘OBJECTIVE: To explore the effect of two dominating signaling pathways, VEGF/KDR and angiopoietins/Tie2, on the formation of new blood vessel in hepatocellular carcinoma (HCC) growth and metastasis. METHODS: RT-PCR and Western blot were employed to evaluate the VEGF/KDR and angiopoietins/Tie2 expression in samples from 23 patients with HCC. Meanwhile, microvessel density (MVD) was determined as a marker of angiogenesis by counting CD34 positive cells with the method of immunohistochemistry. RESULTS: The two pathways were activated in all HCC samples. The expressions of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) were significantly higher (P<0.05) in hepatocellular carcinoma tissues and the margin of the tumor than those in control groups, and so did CD34 positive cells. Although significant difference in the expression of kinase insert domain containing receptor (KDR) and Ang1/Tie2 was not observed in all groups, their distinct high levels were seen in hepatoma and its margin compared with normal and cirrhotic liver. VEGF and Ang2 expressions were seen up-regulated in HCC with vascular invasion and satellite lesion. CONCLUSIONS: The two signaling pathways, VEGF/KDR and angiopoietins/Tie2 are activated in the process of angiogenesis in HCC and modulate the formation of new blood vessels. The imparity of the two signaling pathways' activation is to benefit HCC metastasis. In the two pathways, VEGF and Ang2 may play an important role in the process of angiogenesis, and are necessary indicators for the prognosis and metastasis of HCC. This study provides another clue for the exploration of anti-angiogenic agents.
文摘There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxlainducible factor-1 （HIF-1α）. Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase （PI3K）/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT （pAKT） protein staining than did benign ovarian cystadenoma samples （p 〈 0.01）. The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursulug effective treatment against this disease.
基金supported by the National Natural Science Foundation of China(82004193)CACMS Innovation Fund(CI 2021A00914)the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ14-YQ-007).
文摘Angiogenesis in atherosclerosis(AS)promotes plaque destabilization.miR-126 has a significant role in angiogenesis.Tetramethylpyrazine(TMP)and paeoniflorin(PF)have anti-atherosclerotic effects.However,the miR-126-related mechanisms of TMP and PF combination(TMP-PF)on angiogenesis in AS have not been understood.To explore the mechanism of TMP-PF on angiogenesis in AS targeting miR-126.Human umbilical vein endothelial cells(HUVECs)were assigned into the control,model,TMP-PF,TMP-PF+miR-126 inhibitor,and simvastatin groups.HUVECs were transfected with miR-126 inhibitor or negative control,incubated with oxidized low-density lipoprotein(ox-LDL)to establish AS model,and then treated with TMP-PF or simvastatin.Cell proliferation,migration,and tube formation assays are conducted,and the expression of angiogenesis-related factors were detected by enzyme-linked immunosorbent assay(ELISA)and Western blotting.The expression level of miR-126 was confirmed by polymerase chain reaction(PCR).0x-LDL promoted HUVECs proliferation,migration,and tube formation,downregulated miR-126 expression,and increased the expression of VEGF,VEGFR2,bFGF,and FGFR1.TMP-PF inhibited proliferation,migration,and tube formation,upregulated miR-126 expression and decreased the expression of VEGF,VEGFR2,bFGF,and FGFR1 in ox-LDL-induced HUVECs.However,the effects of TMP-PF on angiogenesis and the expression of miR-126,VEGF,VEGFR2,and FGFR1 were abolished by miR-126 inhibitor.TMP-PF suppressed angiogenesis in AS by regulating miR-126/VEGF/VEGFR2 pathway,which might elucidate the underlying mechanism of TMP-PF in alleviating AS.
基金supported by the National Natural Science Foundation of China(No.81274135)
文摘The effects of tanshinone IIA on the proliferation of the human non-small cell lung cancer cell line A549 and its possible mechanism on the VEGFNEGFR signal pathway were investigated. The exploration of the interaction between tanshinone IIA and its target proteins provides a feasible platform for studying the anticancer mechanism of active components of herbs. The CCK-8 assay was used to evaluate the proliferative activity of A549 cells treated with tanshinone IIA (2.5-80 mu mol/E) for 24, 48 and 72 h, respectively. Flow cytometry was used for the detection of cell apoptosis and cell cycle perturbation. VEGF and VEGFR2 expression were studied by Western blotting. The binding mode of tanshinone IIA within the crystal stmcture of the VEGFR2 protein was evaluated with molecular docking analysis by use of the CDOCKER algorithm in Discovery Studio 2.1. The CCK-8 results showed that tanshinone IIA can significantly inhibit A549 cell proliferation in a dose- and time-dependent manner. Flow cytometry results showed that the apoptosis rate of tested group was higher than the vehicle control, and tanshinone IIA-treated cells accumulated at the S phase, which was higher than the vehicle control. Furthermore, the expression of VEGF and VEGFR2 was decreased in Western blot Finally, molecular docking analysis revealed that tanshinone IIA could be stably docked into the kinase domain of VEGFR2 protein with its unique modes to form H-bonds with Cys917 and pi-pi stacking interactions with Va1848. In conclusion, tanshinone IIA may suppress A549 proliferation, induce apoptosis and cell cycle arrest at the S phase. This drug may suppress angiogenesis by targeting the protein kinase domains of VEGF/VEGFR2. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
基金supported by the National Natural Science Foundation of China,No.81401238,81330016,31171020,81172174 and 81270724the grants from Ministry of Education of China,No.313037,20110181130002+2 种基金a grant from State Commission of Science Technology of China,No.2012BAI04B04the grants from Science and Technology Bureau of Sichuan Province of China,No.2012SZ0010,2014FZ0113,2014SZ0149a grant from Clinical Discipline Program(Neonatology)from the Ministry of Health of China,No.1311200003303
文摘Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.
